The aims of this collaboration are two-fold: First, we intend to investigate the conditions under which homosynaptic long-term depression (LTD) can be elicited in area CA1 and the dentate gyrus of the awake rat. Previous work in the applicant's laboratory has led to the discovery of a form of homosynaptic LTD in brain slices, but there is no information yet available on the extent to which what has been learned can be applied to the awake, functioning brain. The sponsor has a great deal of experience studying another form of 'heterosynaptic' LTD in the awake hippocampus, and therefore provides an ideal environment to investigate the question of whether homosynaptic LTD can be evoked reliably in the functioning brain and how it interacts with heterosynaptic LTD. Second, we intend to examine the hypothesis that the sign and magnitude of activity-dependent synaptic plasticity varies as a function of the recent history of postsynaptic cell activity. It is proposed that cell activity regulates synaptic modifiability via the activity-dependent, cell-wide regulation of high-affinity calcium buffering capacity. In dentate gyrus granule cells, the protein calbindin D28K is thought to function as an important calcium buffer. In the awake rat, we will test the specific hypothesis that increased dentate activity leads to the synthesis of calbindin, and that this increase in calcium buffering capacity reduces the probability and magnitude of LTP in the perforant path-dentate granule cell synapses. The significance of this project is that it is among the first to directly address the question of how synaptic plasticity, thought to be critical for learning and memory, is regulated by the brain.